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Updated: Aug 6, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
SAMM50 rs3761472 causes mitochondrial dysfunction and progression of metabolic dysfunction-associated steatotic liver
Suyeon Kim1, Young Jin Kim2, Nahyun Kim1
1Department of Biomedical Science and Engineering, Konkuk University, Seoul, 05029, Republic of Korea; School of Advanced Biotechnology, Konkuk University, Seoul, 05029, Republic of Korea.
Objectives:
SAMM50 rs3761472 is associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but its functional consequences in vivo remain unclear. We investigated whether this variant disrupts mitochondrial function and promotes MASLD progression.
Methods:
Associations of rs3761472 with MASLD and liver-related traits were evaluated using Korea Biobank Array data. We generated Samm50 knock-in (KI) mice carrying the D110G substitution corresponding to human rs3761472 using CRISPR/Cas9 and assessed hepatic mitochondrial homeostasis and MASLD-related phenotypes in mice fed a normal diet or a high-fat diet.
Results:
In human genetic analyses, rs3761472 was significantly associated with MASLD and higher serum levels of liver injury markers. Samm50-KI mice showed reduced hepatic SAMM50 expression, disrupted mitochondrial organization, impaired mitochondrial respiration and ATP production, increased mitochondrial oxidative stress, inflammatory activation, apoptosis, and liver injury. Following high-fat diet feeding, Samm50-KI mice exhibited greater hepatic lipid accumulation and liver injury, together with more pronounced insulin resistance and glucose intolerance, than wild-type mice.
Conclusions:
Our findings establish rs3761472 as a functional genetic variant linking mitochondrial architecture to metabolic liver disease pathogenesis, with potential relevance as a genetic biomarker for MASLD susceptibility.
